Periodontitis is the leading cause of tooth loss in the U.S. It is thought to be mediated by the interaction of bacteria with host cells leading to the production of destructive proteases. While many different bacteria have been isolated from the tissue of patients with periodontitis, no single bacterial species has emerged as essential to the development of periodontitis and it remains unclear how different bacteria contribute to the pathogenesis of the disease. The major proteases found to be involved in periodontitis come from a class of enzymes called matrix metalloproteinases (MMPs). MMPs all share a function in degradation of extracellular matrix (ECM) proteins. Multiple MMPs have been found to be elevated in the gingival space of patients with periodontitis and therapy with MMP inhibitors has been shown to improve outcomes in patients with periodontitis. Individual bacteria have been shown to induce MMPs using in vitro systems and other bacteria have been shown to produce enzymes, which can activate MMPs or inactivate their inhibitors. Nevertheless, while the role of bacterially induced MMPs in the pathogenesis of periodontitis has become clearer, the mechanisms by which MMP induction may benefit the bacteria remain unknown. Recently, it has been shown that MMPs have substrates beyond ECM proteins and may be involved in immunomodulation through cleavage of cell surface receptors or inactivation of inflammatory cytokines and chemokines. We will outline our systematic plans to examine the association of individual and combinations of bacterial species with pathologic increases in MMPs. Patients with periodontitis and healthy controls will have gingival crevicular fluid examined for the presence of different MMPs and will also undergo identification of bacterial present in the diseased crevices. Based on these results, we will then choose bacterial combinations to test a novel hypothesis: that different microbial communities, causing periodontitis, share the ability to induce and activate MMPs, which in turn protects the community by modulating the host immune response through cleavage of chemotactic chemokines. These studies will be performed using in vitro cell culture and animal models. Results of this application will lead to a better understanding of the complexities of the host-pathogen and pathogen-pathogen interactions and could potentially result in the development new interventions in periodontitis. [unreadable] [unreadable] [unreadable]